X-ray Powder Diffraction of HME solid dispersions

The ability of PVP polymers to maintain molecules in a non-crystalline form has been studied by several groups (Tamaki et al., 2004, Nair et al., 2001, Thybo et al., 2008b, de Villiers et al., 1998).

In this context, X-ray Powder Diffraction (XRPD) measurement was frequently performed to confirm the presence or absence of crystallinity in the SD formulation. Thus, to reconfirm the nature of the prepared HME PVP-based extrudates, their XRPD behaviour was measured. The percentage of crystalline material within the extrudates was calculated based on a calibration curve that could be found in Appendix I (Figure (i)).

3.3.3.4.1. XRPD of HME PCM in PVP K 29-32

Figure 3.24 shows the XRPD diffractograms of HME PCM PVP K29-32 systems. The diffractograms showed halo patterns up to 50% drug loadings. At higher PCM loading i.e. 60%-70%, clear diffraction peaks were noted as anticipated from the opaque appearance of the extrudate at these loadings.

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a) 20%

g)PM20%

e)60%

f)70%

b)30%

2θ degree c)40%

d)50%

PCMPVPK29/32

h)Pure PCM

Figure 3.24: X-ray Diffraction patterns of PCM and PVP K29-32, a) HME 20% PCM, b) HME 30% PCM , c) HME 40% PCM, d) HME 50% PCM, e) HME 60% PCM, f) HME 70% PCM, g) PM 20% PCM and h) Pure

PCM

The diffracted peaks in the X-ray diffractograms of HME 60% and 70% PCM PVP K29-32 (Figure 3.24) corresponded to the initially used polymorphs form, i.e. Form I crystals (Al-Zoubi et al., 2002). The detection of crystalline material for HME 60% PCM-PVP K29-32 and above was due to the use of a relatively low extrusion temperature, i.e. 120 ^oC, which rendered only a certain solid

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solubility limit at about 50% of drug loading in PVP K29-32. However, the reduction of crystal content were still seen in extrudates of 60% and 70% drug loading compared to the PM. The percentage of crystalline PCM is compared to the calculated crystallinity from previous section on MTDSC (Figure 3.11). Table 3.10 summarise the percentage of crystalline PCM detected by using both XRPD and MTDSC methods. It was noted that the calculated percentages of crystalline PCM were in good agreement to that prediction from MTDSC data.

Table 3.10: Percentage crystalline PCM in HME PCM- PVP K29-32

Samples XRPD Crystallinity (%) MTDSC Crystallinity (%)

HME 60% PCM-PVP K29-32 13.72 14.43

HME 70% PCM-PVP K29-32 29.25 29.17

3.3.3.4.2. XRPD of HME PCM in PVPVA 6:4

Figure 3.25 shows the XRPD data of HME PCM in PVPVA 6:4 systems. Unlike PVP K29-32 carriers system of PCM, HME 50% w/w PCM-PVPVA 6:4 gave rise to X-ray diffraction peaks.

This in turn implies that the solubility limit of PCM in PVPVA 6:4 is lower than that in PVP K29-32. Table 3.11 outlines the percentage of crystalline material in HME 50% PCM in PVPVA 6:4.

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PCM PVPVA a)20%

c)40%

b)30%

d)50%

e)PM20%

Figure 3.25: X-ray diffraction patterns of PCM with PVPVA 6:4, a) HME 20% PCM, b) HME 30% PCM , c) HME 40% PCM, d) HME 50% PCM, e) PM of 20 % PCM-PVPVA 6:4

Table 3.11: Percentage of crystal based on Bragg reflection peak from XRPD

Samples XRPD Crystallinity (%) MTDSC Crystallinity (%)

HME 50% PCM-PVPVA 6:4 10.52 8.91

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The excess crystalline material seen in HME 60% PCM PVP K29-32 and HME 50% PCM in PVPVA 6:4 led to the conclusion that the solid solubility of PCM in the presence of PVP K29-32 and PVPVA 6:4 at 120 ^oC were circa 50% and 40% of drug loading, respectively. Interestingly, this observation corresponded to the theoretical estimation in Chapter 3.3.1.2, Table.3.5.

3.3.3.4.3. XRPD of HME CAF in PVP K29-32 and PVPVA 6:4

X-ray Powder diffraction was also used to analyse extrudates of HME CAF in PVP systems. Since the diffracted peaks in the X-ray diffractograms of HME PVP-based CAF systems indicated a different polymorphic form of CAF which was different from the PM of raw CAF, percentage of CAF crystallinity in the HME extrudates was not performed. Thus the discussion below describes only the XRPD characteristic of the HME CAF-PVP based samples without quantification of the crystalline CAF.

HME CAF-PVP K29-32

Figure 3.26 displays the XRPD spectra of CAF, PM and HME of CAF PVP K29-32 systems. A halo pattern was only detected in HME 10% CAF-PVP K29-32.

Figure 3.26: X-ray diffraction patterns of CAF and PVP K29-32, a) HME 10% CAF, b) HME 20% CAF, c) PM of 10% CAF d) commercial CAF as received

In XRPD diffractograms of HME 20% CAF-PVP K29-32, a single characteristic peak at 2θ = 26.86^o was noted which is attributed to Form I CAF (Figure 3.26 (b)). The detection of Form I in the hot processed HME PVP-based extrudates was not unexpected as Form I CAF was reported to

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Intensity

Degree (2θ) a)

b) c)

d)

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be stable at high temperatures (Descamps et al., 2005b, Moura Ramos et al., 2006, Kishi and Matsuoka, 2010). Besides, X-ray diffractogram of HME 20% CAF PVP K29-32 shows a reduction in degree of crystallinity of CAF as compared to its PM. Therefore, it is suggested that CAF dissolves into PVP K29-32 to a minor extent upon heat processing.

Recalling the DSC thermogram of HME 20% CAF PVP K29-32, an anomalous peak and a melting peak were noted at 115 ^oC and 212 ^oC, respectively. The melting peak corresponds to the detection of crystalline trace which is in accordance to the diffracted peak seen in the XRPD diffractogram (Figure 3.26).

HME CAF-PVPVA 6:4

Figure 3.27 presents XRPD diffractograms of HME CAF-PVPVA 6:4 systems. From Figure 3.27, HME CAF-PVPVA 6:4 reveals a halo pattern for HME 10-20% CAF-PVPVA 6:4 systems. This result did not agree with the data obtained from MTDSC and HSM (refer to Chapter 3.3.3.2.2, Figure 3.17 to 3.18) which indicated the presence of crystalline material in both 10% and 20% of HME CAF PVPVA 6:4 system. This might be due to the limited sensitivity of XRPD in detecting low percentage of crystalline material (Saleki-Gerhardt et al., 1994).

Figure 3.27: X-ray diffraction patterns of CAF and PVPVA 6:4, a) CAF, b) PM of 10% c) HME 30%, d) HME 20%, e) HME 10%

Unlike HME CAF-PVP K29-32, a higher amorphous content was noted in HME CAF 20%

PVPVA 6:4 as shown by its halo patterns in XRPD diffractograms. This might be ascribed to the higher extrusion temperature employed in HME PVPVA 6:4 system (i.e. 180 ^oC) as compared to

10 15 20 25 30

Intensity

Degree (2θ) e)

d) c) b)

a)

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PVP K29-32 (i.e. 155 ^oC). Similar to the HME 20% CAF-PVP K29-32, XRPD diffractograms of HME 30% CAF-PVPVA 6:4 system indicated single peaks at 2θ = 26.86^o which was attributed to the Form I CAF (Lehto and Laine, 1998). This is due to the transformation of CAF Form II (raw) to Form I while hot processing at 180 ^oC. Therefore, at 30% CAF loading of HME CAF-PVPVA 6:4, system, there was certain amount of un-dissolved crystalline CAF in the formulations.